The purpose of this program grant is to support a group of investigators attempting to combine genetic and biochemical approaches to examine protein regulation in mammalian cells. We are particularly interested in identifying and characterizing in the mouse, genetic variants which will elucidate the regulatory mechanisms controlling (1) rates of enzyme synthesis and degradation, (2) incorporation of completed enzyme molecules into cell organelles, (3) gene activation during early embryogenesis and (4) the timing of enzyme synthesis during development; and to apply the knowledge gained to human problems, both by developing animal models of specific diseases, such as Chediak-Higashi Syndrome, and by studying genetic components of human disease. In support of these efforts we have established a mouse colony which is developing new inbred and congenic strains of domestic mice and related wild species; and a facility for the measurement of glucuronidase and other enzymes in single mammalian cells. Several of our observations and techniques are now being applied to the study of human disease. These include examining the role of glucuronidase in bladder cancer and the role of aryl hydrocarbon hyyroxylase in cancer of the lung, bladder, colon and kidney.